E2F-dependent accumulation of hEmi1 regulates S phase entry by inhibiting APCCdh1

Hsu, Jerry Y.; Reimann, Julie D.R.; Sørensen, Claus Storgaard; Lukáš, Jiří; Jackson, Peter K.

doi:10.1038/ncb785

Cited by 305 publications

(405 citation statements)

References 48 publications

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“…More importantly, we further demonstrated that ectopic expression of cyclin E led to an increase in the phosphorylation of endogenous Cdh1 ( Figure 4H), whereas depletion of cyclin E resulted in a sharp decrease in endogenous Cdh1 phosphorylation ( Figure 4I). Therefore, consistent with previous reports [25,44,45], these results support a model that the Fbw7/cyclin E signaling pathway potentially regulates the E3 ligase activity of APC Cdh1 by affecting the interaction of Cdh1 with the APC core subunit primarily through regulating Cdh1 phosphorylation status ( Figure 6). …”

Section: Cdk2/cyclin E Directly Phosphorylates Cdh1 At Multiple Sitessupporting

confidence: 81%

Regulation of APCCdh1 E3 ligase activity by the Fbw7/cyclin E signaling axis contributes to the tumor suppressor function of Fbw7

et al. 2013

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Fbw7 and Cdh1 are substrate-recognition subunits of the SCF-and APC-type E3 ubiquitin ligases, respectively. There is emerging evidence suggesting that both Fbw7 and Cdh1 function as tumor suppressors by targeting oncoproteins for destruction. Loss of Fbw7, but not Cdh1, is frequently observed in various human tumors. However, it remains largely unknown how Fbw7 mechanistically functions as a tumor suppressor and whether there is a signaling crosstalk between Fbw7 and Cdh1. Here, we report that Fbw7-deficient cells not only display elevated expression levels of SCF Fbw7 substrates, including cyclin E, but also have increased expression of various APC Cdh1 substrates. We further defined cyclin E as the critical signaling link by which Fbw7 governs APC Cdh1 activity, as depletion of cyclin E in Fbw7-deficient cells results in decreased expression of APC Cdh1 substrates to levels comparable to those in wildtype (WT) cells. Conversely, ectopic expression of cyclin E recapitulates the aberrant APC Cdh1 substrate expression observed in Fbw7-deficient cells. More importantly, 4A-Cdh1 that is resistant to Cdk2/cyclin E-mediated phosphorylation, but not WT-Cdh1, reversed the elevated expression of various APC Cdh1 substrates in Fbw7-deficient cells. Overexpression of 4A-Cdh1 also resulted in retarded cell growth and decreased anchorage-independent colony formation. Altogether, we have identified a novel regulatory mechanism by which Fbw7 governs Cdh1 activity in a cyclin E-dependent manner. As a result, loss of Fbw7 can lead to aberrant increase in the expression of both SCF Fbw7 and APC Cdh1 substrates. Our study provides a better understanding of the tumor suppressor function of Fbw7, and suggests that Cdk2/cyclin E inhibitors could serve as effective therapeutic agents for treating Fbw7-deficient tumors.

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Section: Cdk2/cyclin E Directly Phosphorylates Cdh1 At Multiple Sitessupporting

confidence: 81%

Regulation of APCCdh1 E3 ligase activity by the Fbw7/cyclin E signaling axis contributes to the tumor suppressor function of Fbw7

et al. 2013

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“…Cdh1 is inhibited in all systems by cyclin-Cdk phosphorylation, and is also inhibited by stoichiometric-binding proteins (Emi1 and Acm1). In animals, Emi1 is an E2F transcriptional target, which binds and inhibits Cdh1 [48]; in yeast, Acm1 similarly binds and inhibits Cdh1 [49] and is expressed specifically at G1-S, probably under SBF control [50]. However, Acm1 and Emi1 lack detectable sequence similarity [51].…”

Section: The G1 -S Regulatory Network In Budding Yeast and Animals Hamentioning

confidence: 99%

Evolution of networks and sequences in eukaryotic cell cycle control

Cross

Buchler

Skotheim

2011

Phil. Trans. R. Soc. B

131

114

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The molecular networks regulating the G1 -S transition in budding yeast and mammals are strikingly similar in network structure. However, many of the individual proteins performing similar network roles appear to have unrelated amino acid sequences, suggesting either extremely rapid sequence evolution, or true polyphyly of proteins carrying out identical network roles. A yeast/ mammal comparison suggests that network topology, and its associated dynamic properties, rather than regulatory proteins themselves may be the most important elements conserved through evolution. However, recent deep phylogenetic studies show that fungal and animal lineages are relatively closely related in the opisthokont branch of eukaryotes. The presence in plants of cell cycle regulators such as Rb, E2F and cyclins A and D, that appear lost in yeast, suggests cell cycle control in the last common ancestor of the eukaryotes was implemented with this set of regulatory proteins. Forward genetics in non-opisthokonts, such as plants or their green algal relatives, will provide direct information on cell cycle control in these organisms, and may elucidate the potentially more complex cell cycle control network of the last common eukaryotic ancestor.

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“…It relies on Cdh1, the G 1 -phase-specific adaptor subunit (Wa¨sch et al, 2010), and goes hand in hand with marked decline of Emi1 expression, the main interphase inhibitor of the APC/C (Hsu et al, 2002). Importantly, activation of APC/C-Cdh1 is required for timely destruction of a broad range of APC/C substrates after DNA damage.…”

Section: Introductionmentioning

confidence: 99%

p53- and p21-dependent premature APC/C–Cdh1 activation in G2 is part of the long-term response to genotoxic stress

2010

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The long-term cellular response to DNA damage is controlled by the tumor suppressor p53. It results in cellcycle arrest followed by DNA repair and, depending on the degree of damage inflicted, premature senescence or apoptotic cell death. Here we show that in normal diploid fibroblasts the ubiquitin ligase anaphase-promoting complex or cyclosome (APC/C)-Cdh1 becomes prematurely activated in G2 as part of the sustained long-term but not the rapid short-term response to genotoxic stress and results in the degradation of numerous APC/C substrates. Using HCT116 somatic knockout cells we show that mechanistically premature APC/C activation depends on p53 and its transcriptional target p21 that mediates the signal through downregulation of the APC/C inhibitor Emi1. Cdc14B is dispensable in this setting but might function redundantly. Our data suggest an unexpected role for the APC/C in executing a part of the p53-dependent DNA damage response that leads to premature senescence.

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E2F-dependent accumulation of hEmi1 regulates S phase entry by inhibiting APCCdh1

Cited by 305 publications

References 48 publications

Regulation of APCCdh1 E3 ligase activity by the Fbw7/cyclin E signaling axis contributes to the tumor suppressor function of Fbw7

Regulation of APCCdh1 E3 ligase activity by the Fbw7/cyclin E signaling axis contributes to the tumor suppressor function of Fbw7

Evolution of networks and sequences in eukaryotic cell cycle control

p53- and p21-dependent premature APC/C–Cdh1 activation in G2 is part of the long-term response to genotoxic stress

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